Psychostimulant-induced alterations in vesicular monoamine transporter-2 function: Neurotoxic and therapeutic implications

The vesicular monoamine transporter-2 (VMAT-2) is an important regulator of intraneuronal monoamine concentrations and disposition as this protein sequesters critical cytoplasmic monoaminergic transmitters and contributes to their subsequent exocytotic release. This review primarily discusses the impact of psychoactive drugs (including those with abuse potential) on dopamine (DA)-related VMAT-2 and its function. In particular, the different responses by DA-related VMAT-2 and associated vesicles to plasmalemmal uptake blockers like methylphenidate and releasers like methamphetamine are presented. Recent preclinical findings suggest that vesicular transporter systems are highly regulatable, both by changes in localization as well as alterations in the kinetics of the VMAT-2 protein. The capacity for such shifts in VMAT-2 functions suggests the presence of physiological regulation that likely influences the activity of DA systems. In addition, these findings may contribute to our understanding of the pathogenesis of a variety of DA-related disorders such as substance abuse and Parkinson's disease and also suggest new therapeutic targets for treating such diseases.